The present invention relates to a mass sensor for determining a minute mass of a nanogram (10.sup.-9 g) order, for example, a mass sensor for sensing microorganisms such as bacteria, viruses, and protozoa (immune sensor), and a mass sensor for sensing moisture, toxic substances, or specific chemical substances such as taste components (moisture meter, gas sensor, and taste sensor), and a method for sensing a mass. In particular, the present invention relates to a mass sensor conveniently used for determining the mass of a substance to be sensed by measuring change in resonant frequencies caused by change in the mass of a diaphragm on which a catching substance for catching a substance to be sensed by reacting only with the object of sensing (the substance to be sensed) is applied, and a method for sensing a mass.
Since the mass sensor of the present invention is not limited to the measurement of change in the mass of the catching substance applied on a diaphragm as described above, that is, not limited to the indirect measurement of change in the mass of a diaphragm, but it is naturally possible to sense change in resonant frequency due to change in the mass of the diaphragm itself, the mass sensor can also be used as a thickness gauge for vapor-deposited films or a dew indicator.
Furthermore, even if the mass of the diaphragm is not changed directly or indirectly, the mass sensor of the present invention can also be used as a vacuum gauge, a viscosity meter, or a temperature sensor by placing it in an environment to cause change in resonant frequency, that is, by placing it in a medium environment of gases or liquids having different degree of vacuum, viscosity, or temperature.
Thus, although the mass sensor of the present invention can be used in various applications depending on its embodiments, the same basic principle is also applied to the measurement of change in resonant frequencies of the diaphragm and the resonating portion including the diaphragm.
Recent progress of scientific and medical technologies, and newly developed pharmaceuticals such as antibiotics and chemotherapy drugs have enabled the treatment of various diseases heretofore considered to be difficult to treat. Among what are referred to as diseases, microorganism examinations are essential for the treatment of diseases caused by microorganisms such as bacteria, viruses, or protozoa, to find their pathogens, to clarify their types, and to determine drugs to which they are sensitive.
At present, in the first stage of microorganism examinations, since the cause of a disease and the type of the pathogen can be estimated from the symptoms, various specimens, such as blood, are selected depending on the type of the disease, pathogens present in the specimens are morphologically identified, or antigens or the specific metabolites of pathogens (e.g., toxins or enzymes, etc.) existing in the specimens are immunochemically identified. This process is smeartest, staining, or microscopy used in bacterioscopy, and in recent years, instantaneous identification has become possible by fluorescent antibody staining or enzymatic antibody staining.
Furthermore, the virus serological test, recently used in the detection of viruses, is a method for proving the presence of specific immunity antibodies that appear in the serum of a patient. Examples of the method include the complement fixation reaction in which the presence of antibodies or antigens is determined by adding complements to test blood, and by observing whether the complements react with antigens or antibodies in the blood and fix to the cell membranes of the antigens or antibodies, or destroy the cell membranes.
Except extremely special cases where symptoms have not been seen heretofore, and the disease is caused by a new pathogen which has not been discovered, in the treatment of diseases caused by microorganisms or the like, adequate treatment can be conducted by finding pathogens in an early stage through the microorganism test described above, and the patient can be led to recovery without worsening of the symptoms.
However, with methods such as smeartest, staining, and microscopy, the detection of microorganisms is often difficult depending on their quantities, and time-consuming treatment such as the culture of specimens on an agar is required at need. Also in the virus serological test, since measurements must be performed as a rule during both the acute stage and the convalescent stage for determination from the movement of the quantities of antibodies, there is the problem of time consumption from the point of view of prompt diagnosis.
As seen in complement fixation reaction described above, when a substance to be sensed reacts with a catching substance which catches the substance to be sensed by reacting only with specific substance to be sensed, microorganisms, the mass of the catching substance increases by the mass of the substance to be sensed, even slightly. Such an increase in the mass similarly occurs in the relationship between a catching substance (adsorbing substance) and a chemical substance such as a specific gaseous substance and a smell component, and also applies to the case where a substrate itself without change in the mass is a catching substance, on which a specific substance is deposited or added. On the contrary, when a reaction in which a substance to be sensed caught by a catching substance or the like is released occurs, the mass of the catching substance or the like slightly decreases.
As an example of a method for sensing change in such a small mass, U.S. Pat. No. 4,789,804 discloses, as shown in FIG. 20, a mass sensor 80 comprising a quartz oscillator 81 and electrodes 82, 83 facing the quartz oscillator. When any substance adheres externally to these electrodes 82, 83, the mass sensor 80 senses change in their mass using change in the resonant frequency of the thickness slip oscillation (shear mode oscillation) of the quartz oscillator 81 in the direction of the surface of the electrodes.
Furthermore, FIG. 21 shows a quartz oscillator of a conventional quartz friction vacuum gauge.
However, such a mass sensor 80 has a problem in that since the part to which an external substance adheres and the part for detecting resonant frequency are in the same location, for example, the resonant frequency is unstable when the piezoelectric properties of the mass sensor 80 itself vary due to the temperature of the specimen or change in temperature. Also, if the specimen is a conductive solution, and when the mass sensor 80 is immersed unprotected in the specimen, short-circuit between electrodes may occur. Therefore, the mass sensor 80 must be subjected to insulation such as resin coating.
In order to the solve problems in such a mass sensor 80, the present inventors have disclosed in Japanese Patent Application No. 9-361368 various mass sensors for measuring change in resonant frequencies before and after the mass has been changed when a diaphragm is allowed to oscillate by directly or indirectly changing the mass of the diaphragm. An example is shown in FIG. 19. A mass sensor 30 has a construction in which a resonating portion, composed by joining a connecting plate 33 to a diaphragm 31, and joining a sensing plate 32 having a piezoelectric element 35 arranged on the surface to the connecting plate 33, is joined to the side of a sensor substrate 34 having rectangular sides. In this mass sensor 30, change in the mass thereof can be known easily in a short time by measuring change in the resonant frequencies of the resonating portion mainly due to change in the mass of the diaphragm 31.
However, such a mass sensor 30 has a problem of difference in sensitivity depending on whether the location where the mass of the diaphragm 31 changed is, for example, the central portion or the end portion of the diaphragm 31, even the same amount of change, and improvement for minimizing the difference in sensitivity is demanded. Also, the sensitivity can be improved by making the diaphragm 31 oscillate more easily.